Ishizuka Mayumi, Tanikawa Tsutomu, Tanaka Kazuyuki D, Heewon Min, Okajima Fumie, Sakamoto Kentaro Q, Fujita Shoichi
Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo.
J Toxicol Sci. 2008 Aug;33(3):283-91. doi: 10.2131/jts.33.283.
Warfarin is commonly used worldwide as a rodenticide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. It has been reported that repeated or long-term treatments with this drug cause resistance in wild rodents. However, the mechanism of warfarin resistance in rodents is still not known precisely. Recent studies reported and identified the function of the molecule, vitamin K epoxide reductase complex subunit 1 (VKORC1), which is the main unit of VKOR. An amino acid substitution in VKORC1 is one of the supposed mechanisms of warfarin resistance. An accelerated detoxification system involving cytochrome P450 (CYP) could also cause the rodenticide resistance. Administration of SKF-525A, a potent inhibitor for P450, increased the mortality due to reduction of warfarin metabolism in warfarin-resistant rats. Meanwhile, the appearance of warfarin-resistant rodents has led to the development of the more effective and toxic rodenticide superwarfarin, which is widely used in Europe and the USA. However, animals resistant to this second-generation rodenticide have already been reported in Europe. In this review, we focus on the mechanism and the pleiotropic effects of pesticide resistance in wild rodents.
华法林在全球范围内普遍用作灭鼠剂。它通过抑制维生素K 2,3-环氧化物还原酶（VKOR）的活性来抑制血液凝固。维生素K供应不足会阻碍凝血酶原的产生并导致出血。据报道，用这种药物反复或长期治疗会使野生啮齿动物产生抗药性。然而，啮齿动物对华法林抗药的机制仍未完全明确。最近的研究报道并确定了维生素K环氧化物还原酶复合体亚基1（VKORC1）分子的功能，它是VKOR的主要组成部分。VKORC1中的氨基酸替代是华法林抗药的一种推测机制。涉及细胞色素P450（CYP）的加速解毒系统也可能导致对灭鼠剂产生抗药性。给抗华法林的大鼠施用P450的强效抑制剂SKF-525A，由于华法林代谢减少而增加了死亡率。同时，对华法林有抗药性的啮齿动物的出现促使了更有效且毒性更强的灭鼠剂——超级华法林的研发，这种灭鼠剂在欧洲和美国被广泛使用。然而，欧洲已经报道了对这种第二代灭鼠剂有抗性的动物。在这篇综述中，我们重点关注野生啮齿动物对杀虫剂产生抗药性的机制和多效性影响。
